Patent GB-999582-A (GB)
Title: Trihydroxamic acids
IPC: C07D259/00
Filed: 1961-10-10
Abstract: The invention comprises compounds of the formula <FORM:0999582/C2/1> (wherein R1 is hydrogen, acyl or 2,4-dinitrophenyl and -CO.R2 is acyl or R1 and -COR2 together are succinyl, thus forming a 33-membered ring) and O-acyl derivatives and salts thereof; and their preparation by condensing 3 mols. of 1-amino-5-hydroxylaminopentane or 1-amino-5-nitro-pentane, 2 mols. of a succinic acid or anhydride, or an azide, imide, imidazolide or ester thereof, and 1 mol. of a carboxylic acid which may contain a second carboxyl group or a functional derivative thereof in any suitable order of succession, provided that (a) when 1-amino-5-nitro-pentane is used, the nitro group is reduced to the hydroxylamino group prior to the condensation with an acid or its derivative; (b) when an intermediate product containing an N-hydroxy-N-(b -carboxypropionyl) radical is condensed with 1-amino-5-nitro-pentane or with a 1-amino-5-N-acylhydroxylamino-pentane the intermediate product is converted into a dioxo-oxazine prior to the condensation; and (c) the free amino group of the terminal nitrogen atom in formula (I) is protected by a 2,4-dinitrophenyl group or an acyl group, and, if desired, from the final product the acyl group R1 is split off by hydrolysis or hydrogenolysis and, if desired, the product wherein R1 is a hydrogen atom and COR2 is a b -carboxypropionyl group is intramolecularly condensed to form a 33-membered ring.  The products may be acylated at the terminal nitrogen atom, any O-acyl derivatives formed being converted into the O-unsubstituted N1-acyl compound by means of ammonia; or converted into N-(2,4-dinitrophenyl) derivatives; and COR2 groups can be exchanged and free carboxyl groups esterified.  The products can also be converted into and released from their metal derivatives, e.g. natural ferrioxamines and derivatives thereof formed, for example, by acylation or esterification.  In examples: (1) 1 - amino - 5 - nitropentane and carbobenzoxy chloride give compound II <FORM:0999582/C2/2> this is reduced to compound III <FORM:0999582/C2/3> which is converted into the hydrochloride (1 - benzoylamino - 5 - hydroxylamino - pentane hydrochloride is prepared similarly), product III with succinic anhydride gives compound IV <FORM:0999582/C2/4> this on heating with cyclohexyl-carbodiimide gives compound <FORM:0999582/C2/5> (1 - benzoylamino - 5 - (N - succinyl - hydroxyl - amino) - pentane and N - (51 - benzoylaminopentyl) - tetrahydro - 3,6 - dioxo - 1,2 - oxazine are prepared similarly), this with 5-nitro-1-aminopentane gives compound VI <FORM:0999582/C2/6> (1 - benzoylamino - 5 - [N - (51 - nitropentylamino - succinyl) - hydroxylamino - pentane is prepared similarly), this is reduced to compound VII <FORM:0999582/C2/7> (1 - benzoylamino - 5 - [N - 51 - hydroxylamino - pentylamino - succinyl) - hydroxylamino] - pentane is similarly prepared, and the preparation of the 51-N-monoacetyl derivative and the triacetyl derivative is also referred to). this with succinic anhydride gives compound VIII <FORM:0999582/C2/8> this with 1-amino-5-(N-acetyl-hydroxylamino)-pentane gives compound IX <FORM:0999582/C2/9> or compound VIII with 1-amino-5-(N-succinylmonomethyl ester) - O - acetyl - hydroxylamino - pentane (prepared from compound IV by esterification, acetylation and hydrogenolysis) gives compound IXa <FORM:0999582/C2/10a> compound IX with ketene gives a tri-O-acetate, this on hydrogenolysis gives the free N1-amino compound, and this with ammonia gives 30-methyl - 7,18,29 - trihydroxy - 8,11,19,22,30 - pentaoxo - 1,7,12,18,23,29 - hexaazatriacontane (compound XII), the hydrochloride and acetate of which are described; compound IXa is similarly acetylated, hydrogenolysed and desacetylated; compound XII is converted to the N1-benzoyl-tri-O-benzoyl derivative which with ammonia gives the N1-benzoyl derivative (identical with the corresponding hydrolysate obtained from the O,O1,O11,N-tetrabenzoyl derivative of ferrioxamine B); compound XII with ferric chloride gives ferrioxamine B hydrochloride which is converted to the N-2,4-dinitrophenyl derivative; (2) carbobenzoxychloride and 1-amino-5-nitropentane hydrochloride give 1 - carbobenzoxyamino - 5 - nitropentane, this is reduced to 1 - carbobenzoxyamino - 5 - hydroxylaminopentane (hydrochloride described), this with succinic anhydride gives 1-carbobenzoxyamino - 5 - (N - succinylhydroxylamino) - pentane, this is converted to N-(51-carbobenzoxyaminopentyl) - tetrahydro - 3,6 - dioxo - 1,2 - oxazine, this with 1-amino-5-nitropentane hydrochloride gives 1 - carbobenzoxyamino - 5 - [N - (51 - nitropentylamino-succinyl) - hydroxylamino] - pentane, this on reduction gives 1-carbobenzoxyamino-5-[N - (51 - hydroxylamino - pentylamino - succinyl) - hydroxylamino] - pentane, this with acetic anhydride gives the N1,O,O-triacetyl derivative, this with potassium hydroxide gives the N1-mono-acetyl derivative, this on hydrogenolysis gives 19-methyl-7,18-dihydroxy-8,11,19-trioxo - 1,7,12,18 - tetraaza - nonadecane, the hydrochloride of this with compound V gives compound IX and this is converted to compound XII and this to ferrioxamine B hydrochloride; (3) the iron is removed from the last-named compound with 8-hydroxyquinoline to give compound XII as the hydrochloride; (4) sodium hydroxide replaces the 8-hydroxyquinoline of Example (3); (5) compound XII is converted via the tetra-acetyl derivative to the N1-monoacetyl derivative; (6) ferrioxamine D1 and sodium hydroxide give the product of (5); (7) hydrochloric acid replaces the sodium hydroxide of (6); (8) N-acetyl-ferrioxamine G (obtained from Streptomyces pilosus A21748 (NRRL 2857) and ferric sulphate, as ferrioxamine G hydrochloride and ferrioxamine B hydrochloride, the former then being converted to the required N-acetyl derivative) and sodium hydroxide give 1-acetyl-30-(b -carboxyethyl)-7,18,29 - trihydroxy - 8,11,19,22,30 - pentaoxo - 1,7,12,18,23,29 - hexaaza - triacontane; (9) N-acetyl-ferrioxamine G is converted to the methyl ester and this with sodium hydroxide gives 1-acetyl-30-(b -carbomethoxy-ethyl)-7,18,29-trihydroxy - 8,11,19, 22,30 - penta - oxo - 1,7,12, 18,23,29-hexaaza-triacontane; (10) compound XII hydrochloride and valeryl chloride give the 1-valeryl derivative; and (11) compound XII hydrochloride and stearyl chloride give the 1-stearyl derivative; and other 1-acyl derivatives are prepared similarly.  The desferri-ferrioxamines of the invention, which are stated to affect the metabolism of iron and other metals, and their physiologically tolerable salts, may be made up into pharmaceutical and veterinary compositions with suitable carriers.  They may take the form of tablets, dragees, powders, ointments, creams, suppositories, vials, solutions, suspensions or emulsions, and may contain preserving, stabilizing, wetting or emulsifying agents. Specification 963,904 is referred to.